Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis

Rongjun He, Zhi Hong Yu, Ruo Yu Zhang, Li Wu, Andrea M. Gunawan, Zhong-Yin Zhang

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a Ki of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB.

Original languageEnglish (US)
Pages (from-to)1231-1235
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number12
DOIs
StatePublished - Dec 10 2015

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Keywords

  • antituberculosis
  • mPTPB inhibitor
  • Protein tyrosine phosphatase
  • pTyr mimetics

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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